CN113318275B - 用于牙髓牙本质再生的可降解水凝胶 - Google Patents
用于牙髓牙本质再生的可降解水凝胶 Download PDFInfo
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- CN113318275B CN113318275B CN202110883427.0A CN202110883427A CN113318275B CN 113318275 B CN113318275 B CN 113318275B CN 202110883427 A CN202110883427 A CN 202110883427A CN 113318275 B CN113318275 B CN 113318275B
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- hydrogel
- dental pulp
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- chitosan
- interleukin
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Abstract
本发明涉及一种牙髓和/或牙本质再生的可降解水凝胶，其特征在于所述水凝胶以壳聚糖和二4‑醛基苯甲酸聚乙二醇酯的反应物作为支架材料，所述水凝胶还含有表皮生长因子（EGF）和白细胞介素‑2。本发明的水凝胶具有自我修复功能，可以方便地注射到需要治疗的牙髓腔中，通过表皮生长因子（EGF）、白细胞介素‑2和支架材料的共同协同作用，修复细胞进入牙髓腔并发挥修复作用，从而再生和修复患病牙髓和牙本质。
Description
技术领域
本发明属于医药技术领域，具体涉及一种用于牙髓牙本质再生的可降解水凝胶及其应用。
背景技术
牙齿的大部分生物活性主要依赖于牙髓，目前，用惰性合成材料覆盖或替换，即根管治疗是治疗牙髓疾病的主要途径。较常见的充填材料是杜仲胶，杜仲胶是一种异戊二烯热塑性聚合物。治疗时，将坏死的牙髓取出后，熔化的热牙胶被注入到牙根管中。尽管根管治疗术近年来被广泛应用于牙体治疗，但仍然存在如下弊端：根管治疗后的牙体脆性增加，易折断；根管治疗后的牙齿频繁发生脱色，后期牙科美容手术费用高昂；尚无适用于婴儿的患病牙髓根管治疗方法。而且脱位牙发生牙髓坏死的概率为85-96％，挫入牙发生牙髓坏死的概率为70-100％。被忽视的牙体炎症可能是全身性感染的诱因。
理想情况下，改良的牙髓治疗方法应改善并恢复缺损组织的生物学活性。治疗后的牙髓组织可以进一步诱导或促进牙体结构与功能。当牙本质受到刺激时，成牙本质细胞受损甚至死亡，牙髓组织中未分化的前体细胞向受损部位移行并极化，分化为成牙本质细胞样细胞，在受损伤处相对的髓腔壁上合成修复性牙本质以保护牙髓。Gronthos等发现，从已发育完成的牙齿的牙髓组织中提取的前体细胞具有自我更新和多向分化等成体干细胞的特性，并能诱导形成牙髓-牙本质复合体样结构，从而首次提出了牙髓干细胞的概念。
组织工程和干细胞技术的进步为实现牙髓的原位再生或植入全新合成的生物替代牙髓开辟了新的方向。组织工程方法需要三个关键要素：干细胞，支架(或基质)和生长因子。这些关键要素可用于三种主要治疗策略：1)将新鲜分离或培养单个细胞或小细胞聚集体直接注射或者与可降解支架一起植入到受损组织中；2)先将细胞和支架在体外3D培养，一旦3D共培养复合物达到成熟，将其植入受损组织中；3)原位组织再生，即将支架直接植入受损组织并刺激受损部位自身周围细胞“归巢”以促进局部组织修复。无论哪种策略，干细胞是牙髓牙本质再生不可或缺的一个重要因素。牙源性干细胞作为一种新的成体干细胞群体在再生与修复领域倍受关注，包括牙髓干细胞(DPSCs)、牙周膜干细胞(PDLSCs)、根尖周组织干细胞(SCAP)、脱落乳牙干细胞(SHED)等。
中国授权专利CN104548212B公开了一种促进牙髓及牙本质再生的组合物，包括血小板衍生生长因子PDGF和支架材料，血小板衍生生长因子PDGF为PDGF-BB、PDGF-AB和PDGF-AA中的一种或几种，支架材料为藻酸盐、***胶、瓜尔胶、黄原胶、明胶、几丁质、壳聚糖、壳聚糖醋酸盐、壳聚糖乳酸盐、硫酸软骨素、N，O-羧甲基壳聚糖、葡聚糖、纤维蛋白凝胶、纤维蛋白原、天然血块、甘油、透明质酸、千味素、葡糖胺、蛋白聚糖、淀粉、乳酸、泊洛沙姆、甘油磷酸钠、胶原、糖原、角蛋白丝、合成外科密封剂和粘合剂中的一种或几种。该专利声称可以方便地注射到需要治疗的牙髓腔中，通过血小板衍生生产因子PDGF和支架材料的共同作用，修复细胞进入牙髓腔并发挥修复作用，从而再生和修复患病牙髓和牙本质。
中国授权专利CN110664993B公开了一种纤维蛋白原γ链作为制备牙髓牙本质再生试剂的应用，并提供一种促进牙髓牙本质再生的试剂盒，包括有纤维蛋白原γ链，可作为促进牙髓干细胞成牙本质分化的生长因子，能够显著提高牙髓干细胞成牙本质分化的效率，为促进牙髓本质再生提供了新的方法，具有显著的牙齿再生作用。
现有技术公开了壳聚糖与以二苯甲醛为末端的聚乙二醇混合和，在室温下60秒内就可以快速生成固体含量为4-8%的水凝胶，其机理在于壳聚糖的氨基与聚乙二醇上的醛基之间形成希夫碱键，该水凝胶具有可自我修复并且对许多生化刺激物敏感，例如pH、氨基酸和维生素B6衍生物等。由于该水凝胶的上述优异特性并且属于可降解水凝胶，如能将其用于牙髓牙本质再生，将具有广阔的市场前景。但是，遗憾的是，牙髓干细胞在该水凝胶中增殖情况较差，限制了其应用。
发明内容
基于上述背景技术，本发明所要解决的技术问题在于提供一种用于牙髓牙本质再生的可降解水凝胶及其应用。为了实现本发明的发明目的，拟采用如下技术方案：
本发明一方面涉及一种牙髓和/或牙本质再生的可降解水凝胶，其特征在于所述水凝胶以壳聚糖和二4-醛基苯甲酸聚乙二醇酯的反应物作为支架材料，所述水凝胶还含有0.5-2微克/mL表皮生长因子（EGF）和1-3微克/mL白细胞介素-2，其中壳聚糖和二4-醛基苯甲酸聚乙二醇酯的重量比为1：2-4。
在本发明的一个优选实施方式中，其中接种具有牙髓细胞混悬液。
在本发明的一个优选实施方式中，所述表皮生长因子（EGF）和所述白细胞介素-2的重量比为1：2，该比例为本发明最优选的比例。
在本发明的另一个优选实施方式中，牙髓细胞的接种量为4.0-6.0×106个/g凝胶。
在本发明的一个优选实施方式中，所述水凝胶为注射剂。
本发明另一方面还涉及上述水凝胶的制备方法，其特征在于包括如下步骤：
（1）将壳聚糖溶解在醋酸水溶液中，得到壳聚糖溶液，将二4-醛基苯甲酸聚乙二醇酯溶解在去离子水中得到水溶液，两者混合，在室温下搅拌反应，再加入表皮生长因子（EGF）和白细胞介素-2，即得支架材料；
（2）组织块法培养成人牙髓细胞，胰酶消化传代，传至第五代的牙髓细胞胰酶消化收集细胞，细胞混悬液中接种到支架材料中，37℃，CO2箱过夜，次日使用。
本发明另一方面还涉及上述可降解水凝胶在制备促进牙髓和/或牙本质再生的修复材料中的应用。
有益效果
本发明的水凝胶具有自我修复功能，可以方便地注射到需要治疗的牙髓腔中，通过表皮生长因子（EGF）、白细胞介素-2和支架材料的共同协同作用，修复细胞进入牙髓腔并发挥修复作用，从而再生和修复患病牙髓和牙本质。
具体实施方式
为了进一步理解本发明，下面将结合本发明实施例，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
如无特殊说明，本发明实施例中所涉及的试剂均为市售产品，均可以通过商业渠道购买获得。
实施例1：制备可降解水凝胶
（1）将壳聚糖溶解在醋酸水溶液中，得到3w/w%壳聚糖溶液，将二4-醛基苯甲酸聚乙二醇酯（DF-PEG）溶解在去离子水中得到20w/w%水溶液，25ml DF-PEG水溶液加入到70ml壳聚糖溶液，再加入0.1mg表皮生长因子（EGF）和0.2mg白细胞介素-2，在室温下搅拌反应40秒，即得水凝胶；
（2）组织块法培养成人牙髓细胞，胰酶消化传代，传至第五代的牙髓细胞胰酶消化收集细胞，细胞混悬液按5.0×106个/g凝胶接种，37℃，CO2箱过夜，次日使用，使用之前测试凝胶中活的牙髓细胞的数量，经细胞计数法检测，其中含有5.8×106个/g凝胶。
实施例2：
采用与实施例1相同的制剂，区别在于表皮生长因子（EGF）为0.2mg，白细胞介素-2为0.1mg，使用之前测试凝胶中活的牙髓细胞的数量，经细胞计数法检测，其中含有4.2×106个/g凝胶。
实施例3：
采用与实施例1相同的制剂，区别在于表皮生长因子（EGF）为0.2mg，白细胞介素-2为0.2mg，使用之前测试凝胶中活的牙髓细胞的数量，经细胞计数法检测，其中含有4.6×106个/g凝胶。
比较例1：
采用与实施例1相同的制剂，区别在于不加入表皮生长因子（EGF）而加入0.3mg白细胞介素-2，使用之前测试凝胶中活的牙髓细胞的数量，经细胞计数法检测，其中含有2.2×106个/g凝胶。
比较例2：
采用与实施例1相同的制剂，区别在于不加入白细胞介素-2，而加入0.3mg表皮生长因子（EGF），使用之前测试凝胶中活的牙髓细胞的数量，经细胞计数法检测，其中含有3.3×106/g凝胶。
经过上述实验可以看出，在本发明的水凝胶中加入表皮生长因子（EGF）和白细胞介素-2，两者协同作用有助于牙髓细胞在其中的存活。为了进一步验证本发明的水凝胶在促进牙髓牙本质再生中的作用，本发明设计了如下实验。
实施例4：药效学实验
取20只80gBALB/C裸鼠，动物随机分为术后5d和10d观察组，每组10只。实验选用上颌两颗第一磨牙。左上第一磨牙为牙髓细胞实验组；右上第一磨牙为空白对照组。
实验组洞内注射实施例1所制备的水凝胶，对照组洞内接种加入含有1微克/mL表皮生长因子（EGF）和2微克/mL白细胞介素-2的成人牙髓细胞混悬液，然后在其上覆盖无菌硝酸纤维素膜，以高强度玻璃离子粘固剂封闭窝洞。分别磨低上颌左右两侧第一磨牙的牙尖，以降低对充填物的咀嚼压力。无菌生理盐水清洗口腔，术后给予软食。
术后5d，实验组牙髓-牙本质复合体开始显示一定的修复反应，尚未在修复性牙本质与两侧髓腔壁上的修复性牙本质之间形成桥样结构，对照组未能显示任何修复反应。
术后10d，实验组牙髓-牙本质复合体显示良好的修复反应，修复性牙本质与两侧髓腔壁上的修复性牙本质相连接，形成桥样结构，高柱状的成牙本质细胞样细胞沿着其排列成行，这一结构成为阻止外界刺激进入牙髓的屏障。对照组未能显示良好的修复反应，炎症反应涉及大部分冠髓，牙髓内出现弥散的骨样牙本质。
以上描述了本发明优选实施方式，然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。
Claims (7)
1.一种牙髓和/或牙本质再生的可降解水凝胶，其特征在于，所述水凝胶以壳聚糖和二4-醛基苯甲酸聚乙二醇酯的反应物作为支架材料，所述水凝胶还含有0.5-2微克/mL表皮生长因子EGF和1-3微克/mL白细胞介素-2，其中壳聚糖和二4-醛基苯甲酸聚乙二醇酯的重量比为1：2-4。
2.根据权利要求1所述的水凝胶，其特征在于，接种具有牙髓细胞混悬液。
3.根据权利要求2所述的水凝胶，其特征在于，所述牙髓细胞的接种量为4.0-6.0×106个/g凝胶。
4.根据权利要求1所述的水凝胶，其特征在于，所述水凝胶为注射剂。
5.根据权利要求1所述的水凝胶，其特征在于，所述表皮生长因子EGF和所述白细胞介素-2的重量比为1：2。
6.权利要求1-5任意一项所述水凝胶的制备方法，其特征在于，包括如下步骤：
（1）将壳聚糖溶解在醋酸水溶液中，得到壳聚糖溶液，将二4-醛基苯甲酸聚乙二醇酯溶解在去离子水中得到水溶液，两者混合，在室温下搅拌反应，再加入表皮生长因子EGF和白细胞介素-2，即得支架材料；
（2）组织块法培养成人牙髓细胞，胰酶消化传代，传至第五代的牙髓细胞胰酶消化收集细胞，细胞混悬液中接种到支架材料中，37℃，CO2箱过夜，次日使用。
7.权利要求1-5任意一项所述可降解水凝胶在制备促进牙髓和/或牙本质再生的修复材料中的应用。
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